Tetrahydronaphthylalkanoic acids and their derivatives

ABSTRACT

Novel tetrahydronaphthylalkanoic acids and their derivatives are described. Therapeutic compositions and method of treatment of inflammation is also disclosed.

United States Patent Diamond et al.

TETRAHYDRONAPHTHYLALKANOIC ACIDS AND THEIR DERIVATIVES Inventors: JuliusDiamond, Lafayette Hill;

George Henry Douglas, Paoli, both of Pa.

William H. Rorer, Inc., Fort Washington, Pa.

Filed: Dec. 6, 1973 Appl. No: 422,491

Related US. Application Data Division of Ser. No. 268,745, July 3, 1972,Pat. No. 3,829,467.

Assignee:

U.S. Cl. 260/559 R; 260/558 D; 260/559 P; 260/562 A; 260/562 B; 260/562P lnt. Cl. C07c 103/22 [451 July 1, 1975 [58] Field of Search 260/559 R,558 D, 559 P, 260/562 A, 562 B, 562 P References Cited FOREIGN PATENTSOR APPLICATIONS 677,597 6/1968 South Africa OTHER PUBLICATIONS Oka,Chemical Abstracts, Vol. 55, C01. 24656 (1961).

Primary ExaminerC. Davis Attorney, Agent, or Firm-James A. Nicholson [57] ABSTRACT 20 Claims, No Drawings TETRAHYDRONAPHTHYLALKANOIC ACIDS ANDTHEIR DERIVATIVES CROSS-REFERENCE TO RELATED APPLICATIONS This is adivision of application Ser. No. 268,745, filed July 3. 1972, now US.Pat. No. 3,829,467.

SUMMARY OF THE INVENTION This invention describes novel hydroxy, haloand thiotetrahydronaphthylalkanoic acids and their derivatives and theiruse in therapeutic compositions. In addition, this invention describesthe preparation of these hydroxy, halo andthiotetrahydronaphthylalkanoic acids and their derivatives. When thecompounds of this invention are administered to mammals, they affordsignificant treatment for the relief of inflammation and associated painand fever.

They further provide analgesic and antipyretic methods for the reliefand treatment of pain and fever.

BACKGROUND OF THE INVENTION Continued studies have been carried out inresearch to develop drugs which would significantly inhibit thedevelopment of inflammation and relieve the pain and fever associatedwith it. Much of this effort has been carried out in the steroid field;however, there have been compounds developed which are non-steroidal vand have included such as the alkanoic acids derived from thecycloalkylphenyl ring system.

We have unexpectedly found that when a hydroxy, halo, or thio group orderivative thereof is present in the a-position of the side chain of asubstituted tetrahydro-Z-naphthylacetic acid molecule, pharmacologicalproperties exist in the molecule which are useful for the relief andinhibition of inflammation conditions.

We have also found that the compounds of this invention are effective inthe treatment of inflammation and the control of arthritic conditionsassociated with inflammation.

We have further found that a-hydroxy, halo andthiotetrahydro-Z-naphthylacetic acids and their derivatives are novel.

We have also found that the compounds of this invention possess usefulanalgesic and antipyretic properties and are useful in the treatment ofpain and fever.

We have still further found an entirely new class of antiinflammatory,analgesic and antipyretic pharmaceutical compositions which contain ana-hydroxy, halo or thiotetrahydro-Z-naphthylacetic acid or derivativethereof as active ingredient.

We have also found a convenient method for synthesizing these compounds.

DESCRIPTION AND PREFERRED EMBODIMENTS This invention comprises a classof novel chemical compounds which are 5,6,7,8-tetrahydro-2-naphthylacetic acids or derivatives to which is attached a hydroxy,hydroxy derivative, halo, mercapto, or thio derivative at the a-positionof the acetic acid side chain. Also the tetrahydronaphthyl ring mayfurther be substituted.

This invention also describes a new method for treating inflammation aswell as pain and fever and also novel therapeutic compositions.

The compounds of this invention can be represented by the genericstructure which is described by the general formula I where:

R is hydrogen,

alkyl, halo, amino, acylamino, mono and diloweralkylamino, mercapto,acylthio, hydroxy, loweralkoxy, aryloxy, acyloxy, haloloweralkyl,

cyano, acetyl or benzoyl;

R is hydrogen or loweralkyl;

X is hydroxy,

acyloxy, loweralkanesulfonyloxy, arylsulfonyloxy, halo, mercapto,acylthio;

Z is hydrogen,

-OH, loweralkoxy, arloweralkoxy, -NH loweralkylamino, diloweralkylamino,cycloloweralkylamino,

(where A is loweralkylidenyl or heteroloweralkylidenyl),

OM (where M is an alkali, alkaline earth or aluminurn metal or anammonium salt).

The preferred position for substitution is the 4- position.

The preferred compounds of this invention are described by formula Iwhere R is in the 4-position and R; is hydrogen.

The more preferred compounds are those where R is 4-halo or 4-nitro, R ais hydrogen and X is hydroxy or halo.

The most preferred compounds are those where R is 4-halo, R a ishydrogen, X is hydroxy or chloro and Z is -Ol-I, amino,diloweralkylamino and OM.

4 The compounds of this invention contain an asym- A nitro glyoxylatemay be hydrogenated to the corremetric carbon atom in the acid sidechain. As a result, sponding amine. the above compounds of formula I maybe obtained as racemic mixtures of their dextro and levorotatoryisomers. It is to be understood that said (1 and 1 iso- 5 mers as wellas the (11 mixtures thereof are embraced Q within the scope of thisinvention. 6

The compounds of this invention may be prepared from known startingmaterials. References to specific starting materials are given whereapplicable or the fol- 1O lowing methods of synthesis may be used whereappro- NO prlate.

Friedel-Crafts condensation of 5,6,7,8- tetrahydronaphthlene with analkyl (preferably t-butyl) or aralkyl oxalyl chloride in the presence ofanhydrous 15 aluminum chloride results in 5,6,7,8-tetrahydro-2- Inaphthylglyoxylate. This may then be reacted with an C' alkyl Grignardreagent to form the a-alkyl-5,6,7,8- tetrahydro-2-naphthylglycolate orit may be reduced to the glycolate by catalytic hydrogenation withplatinum 20 oxide or under sodium borohydride conditions. 2

, O U l A ll c1 icook" w r C-COOR" Al Cl 3 l R MgX U CH COORAppropriately desired end products having various R 40 An amino compoundmay be diazotized and heated substituents can be prepared at variousstages of the in an aqueous medium to form the hydroxy compoundsynthesis by using suitable reactions in order to convert or heated inan alcohol to form the alkoxy compound. one group to another. Thus, forexample, the glyoxylate The hydroxyl group may also be alkylated withloweralmay be alkylated, halogenated or nitrated to obtain kyl halidesor sulfates to the alkoxyl group or acylated substitution in the4-position. with loweracyl chlorides or anhydrides to the acyloxy COOR"NO 0 2 l LCOOR" COOR" Hal -COOR" C) Alk compound in the presence of atertiary amine such as pyridine.

R"Cl or R"COCl pyridine ll CCO0R" OR" (COR") An amino compound may bemonoor dialkylated 35 with loweralkyl halides or sulfates or acylatedwith loweracyl chlorides or anhydrides.

O 0 I H g I C- COOR H -COOR mom by I H l! V l I -C C0OR|| C COOR|| V'QNHCOR" v N(R") An amino compound may be diazotized followed by aSandmeyer type reaction to yield the halo group.

O 0 H H C-COOR HNO CO0R" O #2 CuBr NH r

HNO

CuI

l C-COOR" C-COOR" o (I An amino compound may also be diazotized to thediazonium fluoroborate which is then thermally decomposed to thecorresponding fluoro compound. HNO 5400p" pound.

I NH

2 It may further be diazotized and followed by addition of cuprouscyanide to obtain the cyano compound.

I "C-COOR" HNO HBF

4 E COOR" N BF CCOOR" -COOR" An aminoglyoxylate may be diazotizedfollowed by 1 reaction with potassium ethylxanthate followed by hy-C-COOR" drolysis to obtain the mercaptoglyoxylate which can beesterified to a mercapto glyoxylate. This, in turn, can be loweralkylated to the lower alkylthio and oxidized NH to the loweralkylsulfinyl and lower alkylsulfonyl 2 groups or acylated to theacylthio compounds.

i 1 HNO C-COOR" KSCSOC H 2) NaOH SH 1: o (\l 5 S a O L) U o: g V

l J-COOR" H 0 C-COOR" v C- COOR" l 2 SCOR" A halo compound in which halois chloro or bromo or iodo may be reacted with cuprous cyanide inquinoline at about 150C to produce a cyano compound: C-COOR" I C-CO0R"i-lal Hal 0 CuCN -COOR" i-COOR" I CN 0 CH l. a J or reacted withtrifluoromethyliodide'and copper pow- The= substituted 'glyoxylate' maybe selectively reder at about 150C in dimethylformamide to obtain aduced to the glycolate or treated'as above with aGrigntrifluoromethylglyoxylate or lactate: [as described in ard reagentto form an a-alkylgly'colate.

ll 7 c-cooR" H-COOR" Tetrahedron Letters: 47, 4095 (1959)] Reaction of a5,6,7,8-tetrahydro*Z-naphthylglycolate I ester with a nitrogen base suchas ammonia, loweralk- O x i ylamine, diloweralkylamine,cycloloweralkylamine, a

H v, nitrogen containing hetero compound such as piperi- C'COOR dine,morpholine, piperazine, hydroxylamine and by drazine gives thecorresponding amide, hydroxamic acid, or hydrazide.

, V v Ha] r v The 5,6,7,8-tetrahydro-2-naphthylglycolate esters may behydrolyzed to the corresponding glycolic acids. Reaction of theglycolate ester or glycolic acid with an acyl chloride XCl or acylanhydride XOX' in the pres- I CF 1 i ence of a tertiary amine such aspyridine, picoline, or

I quinoline results in the formation of an acyloxy com- Cu pound.Examples of XCl and X'OX include acetyl chloride, acetic anhydride,propionyl chloride, butyryl chloride, succinic anhydride, maleicanhydride, f A I phthalic anhydride, benzoyl chloride, benzoic anhy- Ahaloglyo'x-ylate may also be'reacted with cuprous. dride, benzylchlorocarbonate, ethyl chlorocarbonate, methanesulfina'te-in quinoli'ne'atabdutl SOlCtd obtain dime thylcarbamyl chloride, dibutylcarbamylchloride,

a methylsu'lfonylglyoxylatei benzenesulfonyl chloride, methanesulfonylchloride.

responding substituted 5,6,7,S-tetrahydro-Z-naphthyla-halo acetate isprepared.

(3H 1- COOR" Ta] C-COOR" l where R" is lower alkyl; and I Hal is chloro,bromo or iodo.

Reaction of a 5,6,7,8-tetrahydro-2-naphthyl-asulfonate compound with ametal halide (preferably an alkali halide) also results in thecorresponding a-halo compound.

where Z is as described on page 3.

The corresponding 5,6,7,8-tetrahydro-2-naphthyl-ahaloacetic acid may beprepared by heating the ester with acetic acid containing thecorresponding hydrogen halide.

where R" is lower alkyl.

The substituted 5,6,7,S-tetrahydro-2-naphthyl-a-fluoro compoundsmay alsobe obtained from the corresponding a-iodo, a-bromo or a-chloro compoundsby reaction with potassium fluoride at about l30-200C.

C:@- iz-cooR" The acid addition salts may be formed by the action of oneequivalent of a suitable base with the substituted5,6,7,8-tetrahydro-Z-naphthyl-a-haloacetic acid. Suitable bases thusinclude for example the alkali metal alkoxides such as sodium methoxide,etc., and the alkali metal and alkaline earth metal hydroxides,carbonates, bicarbonates, etc. (such as sodium hydroxide, potassiumhydroxide, calcium hydroxide, potassium carbon ate, sodium bicarbonate,magnesium bicarbonate, etc.). Also, the aluminum salts of the instantproducts may be obtained by treating the corresponding sodium salt withan appropriate aluminum complex such as aluminum hydroxy chloridehexahydrate, etc. The ammonium salts may be made by reaction with thecorresponding amine such as methylamine. diethylamine,B-hydroxyethylamine, piperazine, piperidine, a-methylbenzylamine.cyclohexylamine, triethylamine, phenethylamine. etc.

Tel C-COOH tllal -C -COOM Reaction of a substituted5.6,7,8-t'etrahydro-2- naphthyl-a-halo acetate with a nitrogen base suchas ammonia, loweralkylamine, diloweralkylamine, cy cloloweralkylamine, anitrogen containing h'etero compound such as piperidine. morpholine,piperazine results in the corresponding amide. The acetate with hydroxyamine gives the corresponding hydroxamic acid, and with hydrazine givesthe corresponding hydrazine.

(where B is loweralkylidenyl or heteroloweralkylidenyl),

NHOH or The 5,6,7,8-tetrahydro-2-naphthyl-oz-halo acetamides,acethydroxamic acids, and acethydrazides, can be prepared from thecorresponding glycolamides with thionyl halides according to the methodof l. A. Smith, Chem. Berichte 7lB:634 1938).

The substituted 5,6,7,8-tetrahydro-2-naphthyl-ahalo acetic acids andacid derivatives such as their salts, amides or esters may be reactedwith various nucleophilic reagents which will replace the a-halogengroup. Thus for example, an alkali hydrosulfide or an alkalithioalkanoate may be reacted to obtain an a-mercapto or a-acylthiocompound. Other groups which may also react in this manner include suchas an alkali thiobenzoate, alkali loweralkyl-xanthate, thiourea, alkalithiocyanate, alkali thiosulfate, alkali loweralkylmercaptide, alkalisulfite or an alkali sulfinate. This may also be carried out on thea-sulfonate compounds to obtain the same product.

The 5,6,7,8-tetrahydro-2-naphthyl-a-mercapto acetic acids may then bereacted with a loweralkyl chlorocarbonate, an alkali isocyanate in thepresence of hydrogen chloride, 21 loweralkylcarbamyl chloride, adiloweralkylcarbamyl chloride or converted to the metal salt which willreact with a carbamyl chloride to form the correspondinga-mercaptoacetic acid derivatives. The a-mercapto acetic acid may alsobe reacted with succinic anhydride, maleic anhydride or phthalicanhydride to form the corresponding derivative.

The 5,6,7,8-tetrahydro-2-naphthyl-oz-loweralkylmercapto acetic acid mayfurther be oxidized to the loweralkylsulfinyl and loweralkylsulfonylgroups.

In an analogous manner the various a-mercaptoacetates,a-mercaptoacetamides and a-mercaptoacetic acid salts may be preparedfrom the corresponding a-haloacetates, a-haloacetamides andoz-haloacetic acid salts.

Whenit is desired to have substitution in other than the 4-position itis convenient to carry out the original Friedel-Crafts reaction on a lor3-substituted 5,6,7,8- tetrahydronaphthlene which will result indirecting the introduction of the glyoxylate side chain to the orthoposition. Conversion may then be carried out as above to obtain thatsubstituent which is desired. Thus, for example, a lor 3-methyl, halo oracylamino compound may be subjected as above to a Friedel-Craftsreaction using t-butyl oxalyl chloride to obtain the correspondingZ-naphthylglyoxylate which in turn may then be reduced to the glycolate.Deacylation of the amino compound may be carried out which in turn maybe diazotized and converted to several groups as above. Conversion ofthe substituted glycolate compounds to the corresponding a-hydroxyderivatives, a-halo, a-mercapto and a-thio derivatives may be carriedout as above. The acids, salts, amides and esters may also be formed aspreviously outlined.

Of course it will be understood by one skilled in the art thatvariations in the above procedures can be employed which will providethat sequence of reactions which will result in the desired product.

The products of this invention are obtained as racemic mixtures of theirdextro and levorotatory isomers since the oz-carbon of the side chain isasymmetric. These may be resolved into the dextro and levorotatoryoptical isomers by conventional methods.

One method of resolution that may be employed is combining the racemiccompound with an optically active compound by salt formation, esterformation, or amide formation to form two diastereomeric products. Ifthe instant acids are added to an optically active base, then twodiastereomeric salts are produced which possess different properties anddifferent solubilities and can be separated by fractionalcrystallization. When the salts have been completely separated byrepeated crystallization, the base is split off by acid hydrolysis andthe pure (1 or 1 acids are obtained. Preferably, the acetic acid isreacted in alcoholic or acetone solution with an equivalent amount ofthe optically active primary, secondary or tertiary amine such ascinchonidine, cinchonine, quinine, ephedrine, a-methylbenzylamine,sec-butylamine, sec-amylamine, etc. The

diastereomeric amine salts produced thereby, are separated by fractionalcrystallization and each optically active salt is hydrolyzed with dilutemineral acid to produce the dextro or levo form of that acetic acid.Each optical isomer may be reacted then with XCl or XOX to produce thecorresponding optically active alcoholic derivative. Alternatively, analkanoate ester may be reacted with an optically active primary orsecondary amine such as ephedrine, a-methylbenzylamine, secbutylamine,etc., to produce a mixture of diastereomeric acetates which may beseparated by fraction crystallization. Each optically active amide maybe hydrolyzed with mineral acid to its respective optically active acid.

Alternatively, an acetate may be reacted with an optically activealcohol such as l-menthol or d-borneol, or l-a-methylbenzylalcohol, toproduce a mixture of diastereomeric acetate esters which may beseparated by fractional crystallization. Each optically active ester maybe hydrolyzed with mineral acid or alkali to its respective opticallyactive acid. The optically active acids can also be recovered from thea-methylbenzyl esters by hydrogenolysis in the presence of palladium. Inthis manner the a-oxy, halo or thio isomers may be pre pared.

We have found that the compounds of this invention exercise a usefuldegree of anti-inflammatory activity in mammals and are effective in thetreatment of associated pain and fever and in like conditions which areresponsive to treatment with anti-inflammatory agents. In general, thecompounds of this invention are indicated for a wide variety ofmammalian conditions where the symptoms of inflammation and associatedfever and pain are manifested. Exemplary of such conditions are:rheumatic diseases such as rheumatoid arthritis, osteoarthritis andother degenerative joint diseases; softtissue rheumatism such astendinitis; muscular rheumatism such as sciatica; pain and inflammationassociated with dental surgery and similar human and veterinary diseaseconditions exhibiting the foregoing symptoms requiring the use of ananti-inflammatory, analgesic and/or an antipyretic agent.

For these purposes, the compounds of this invention are normallyadministered orally, topically, parenterally or rectally. Orally, thesemay be administered in tablets, capsules, suspensions or syrups; theoptimum dosage, of course, depending on the particular compound beingused and the type and severity of the condition being treated. In anyspecific case the appropriate dosage selected will further depend onfactors of the patient which may influence response to the drug; forexample, general health, age, weight, etc. Although the optimumquantities of the compounds of this invention to be used in such mannerwill depend on the compound employed and the particular type of diseasecondition treated, oral dose levels of preferred compounds whenadministered to a mammal in dosages of 0.5 to 100 milligrams perkilogram of body weight per day are particularly useful. The preferredrange is 0.5 to 15 mg/kg. Comparative dosages may be used in topical,parenteral or rectal administration.

Dosage forms may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents; for example, sweetening agents,flavoring agents, coloring agents, preserving agents, etc. Further, theactive compounds or their derivatives may be administered alone or inadmixture with antacids such as sodium bicarbonate, magnesium carbonate,magnesium hydroxide, aluminum hydroxide, magnesium silicate, etc., andnon-toxic pharmaceutically acceptable excipients. Such excipients maybe, for example, inert diluents such as calcium carbonate, lactose,etc., granulating and disintegrating agents; for example, magnesiumstearate, talc, etc., binding agents; for example, starch gelatin, etc.,suspending agents; for example, methylcellulose, vegetable oil, etc.dispersing agents; for example, lecithin, etc., thickening agents; forexample, beeswax, hard paraffin, etc., emulsifying agents; for example,naturallyoccurring gums, etc., and non-irritating excipients; forexample, cocoa butter and polyethylene glycols.

Various tests in animals can be carried out to show the availability ofthe 5,6,7,8-tetrahydro-2- naphthylacetic acids and derivatives of thisinvention to exhibit reactions that can be correlated withantiinflammatory activity in humans. One such test is the CarrageenanPaw Edema test, which shows the ability of the instant compounds toinhibit edema induced by injection of an inflammatory agent such ascarageenan into the tissues of the paw of a rat against noninflammaedcontrols. This carageenan testing method is known to correlate well withanti-inflammatory activity in humans and is a standard test used todetermine anti-inflammatory activity. This correlation can be shown bythe activities of compounds known to be clinically active including suchas aspirin, phenylbutazone, cortisone, hydrocortisone and prednisolone.In view of the results of this test, the 5,6,7,8-tetrahydro-2-naphthylacetic acids and derivatives can be considered to be activeanti-inflammatory agents.

One method for measuring the pain threshold of the compounds of thisinvention is the Randall-Selitto test. Analgesic activity is shown byantinociceptive testing of the inflammed foot of rats and a measurementof their pain response:

Antipyretic assay is carried out by yeast-induced fever tests ofsubcutaneously injected rats. The measurement of rectal temperature iscarried out to determine the response by the test compounds.

In view of the results of the above tests, the 5,6,7,8-tetrahydro-2-naphthylacetic acids and derivatives of this invention areconsidered to have valuable analgesic and antipyretic properties.

Other tests which can be correlated to show significant activities arethe phenylquinone writhing test for analgesia, polyarthritis in rats andultra-violet erythema in guinea pigs.

The following are detailed examples which show the preparation of thecompounds of this invention. They are to be construed as illustrationsof said compounds and are not intended to be limitations thereof.

EXAMPLE I Ethyl 5,6,7,8-tetrahydro-Z-naphthylglyoxylate5,6,7,8-Tetrahydro-2-naphthlene (0.33 mole) and 50.5 g. (0.37 mole) ofethyl oxalyl chloride are dissolved in 200 ml. of dryl,1,2,2-tetrachloroethane. Anhydrous aluminum chloride 52 g. (0.39 mole)is added in small portions to the reaction mixture with stirring over 2hours. During the addition, the temperature of the mixture is maintainedbetween 1618C. The mixture is stirred for an additional hour and allowedto stand overnight. The solution is then slowly poured into 1500 ml. oficed saline solution with stirring. After standing, two layers form. Theaqueous layer is extracted with 500 ml. of ether and the ether extractis combined with the organic layer which is dissolved in 1500 ml. ofether and separated. The ether solution is washed with X 100 ml.portions of a 1:1 mixture of saturated sodium chloride solution and 10percent HCl solution, and 5 X 100 ml. portions of water. The ethersolution is then dried over anhydrous magnesium sulfate for 1 hour andfiltered. The solvents are removed by distillation under reducedpressure and the residue distilled to obtain ethyl 5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl oxalyl chloride in the above example is replaced with methyloxalyl chloride, propyl oxalyl chloride, i-propyl oxalyl chloride,t-butyl oxalyl chloride, or benzyl oxalyl chloride then the productobtained is the methyl, propyl, i-propyl, t-butyl, or benzyl ester of5,6,7,8-tetrahydro-2-naphthylglyoxylate.

EXAMPLE 2 Ethyl 4-chloro-5 ,6,7,8-tetrahydro-Z-naphthylglyoxylate Ethyl5,6,7,8-tetrahydro-2-naphthylglyoxylate (0.38 mole) and 6.1 g. of iodine(0.048 mole) are dissolved in 100 ml. of carbon tetrachloride. To thissolution is added a solution of 40.4 g. (0.57 mole) of chlorinedissolved in 365 ml. of carbon tetrachloride over a period of 2 hours.During the addition, the temperature of the reaction mixture ismaintained at 0C. The mixture is stirred for 3 hours and allowed tostand with gradual warming to room temperature over hours. The solventis removed by distillation under reduced pressure. The residue isfractionally distilled to obtain ethyl 4-chloro-S,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 5,6,7.8-tetrahydro-2-naphthylglyoxylate in the above exampleis replaced with the esters of Example then the corresponding product isprepared.

EXAMPLE 3 When bromine is used in place of chlorine in Example 2, thecorresponding products are obtained.

EXAMPLE 4 Ethyl 4-nitro-5,6,7,S-tetrahydro-Z-naphthylglyoxylate Ethyl5,6,7,8-tetrahydro-2-naphthylglyoxylate (0.066 mole) is added toice-cold concentrated sulfuric acid (18 ml) and stirred with cooling for5 minutes. Concentrated nitric acid (Sp. O. 1.51) (2.5 ml) is addeddropwise, maintaining the temperature between 30 and 40 by water coolingif necessary. After addition of the nitric acid is complete, the mixtureis stirred for one-half hour, then poured into water. The mixture ismade alkaline with sodium hydroxide,- then extracted with ether. Theether extract is washed, dried over sodium sulfate, evaporated and theresidue is fractionally distilled to obtain ethyl4-nitro-5,6,7,8-tetrahydro-2- naphthylglyoxylate.

When ethyl p-cyclohexylphenylglyoxylate in the above example is replacedby the esters of Example 1, then the corresponding product is prepared.

EXAMPLE 5 Ethyl 4-trifluoromethyl-5,6,7,8-tetrahydro-2-naphthylglyoxylate To a solution of 0.01 moles of ethyl 4-bromo-5,6,7,8-tetrahydro-2-naphthylglyoxylate in 50 ml. of dimethylformamide is added0.15 moles of trifluoromethyl iodide and 0.02 g. of copper powder. Thereaction is shaken in a sealed tube for 5 hours at 140C, cooled, andthen filtered and evaporated in vacuo. 200 ml. of water is added to theresidue and extracted with ether. The ether extract is dried, evaporatedto dryness and distilled to obtain ethyl 4-trifluoromethyl-5,6,7,8-tetrahydro-2-naphthylglyoxylate.

When ethyl 4-bromo-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 3then the corresponding product is obtained.

EXAMPLE 6 Ethyl 4-amino-5,6,7,8-tetrahydro-Z-naphthylglyoxylate EXAMPLE7 Ethyl 4-methylamino-5,6,7,8-tetrahydro-2- naphthylglyoxylate To asolution of 0.01 moles of ethyl 4-amino-5,6,7,8-tetrahydro-2-naphthylglyoxylate in ml. of acetone is added 0.1 moles ofmethyl iodide. The reaction mixture is stirred overnight at roomtemperature, filtered and concentrated. The residue is distilled toobtain ethyl 4-methylamino-5 ,6,7 ,8-tetrahydro-2- naphthylglyoxylate.

When ethyl 4-amino-5 ,6,7 ,8-tetrahydro-2- naphthylglyoxylate in theabove example is replaced by equimolar amounts of the compounds ofExample 6, then the corresponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyl iodide andpyridine in place of acetone, then the product prepared is ethyl4-acetylamino-5,6,7,8- tetrahydro-2-naphthylglyoxylate.

EXAMPLE 8 Ethyl 4-dimethylamino-5 ,6,7 ,8-tetrahydro-2-naphthylglyoxylate A solution of 0.005 moles of ethyl 4-nitro-5,6,7,8-tetrahydro-2-naphthylglyoxylate and 1.6 ml. of 37 percent formaldehydein 50 m1. of methanol is shaken with hydrogen over 0.5 g. of 5 percentpalladium-oncharcoal at 42 lbs. and 27C until 5 moles of hydrogen areabsorbed. The catalyst is filtered off and the filtrate is evaporated invacuo. The residue is then distilled to obtain ethyl4-dimethylamino-5,6,7,8-tetrahydro-2- naphthylglyoxylate.

When ethyl 4-nitro-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 4.then the corresponding products are obtained.

EXAMPLE 9 Ethyl 4-cyano-5,6,7,8-tetrahydro-2-naphthylglyoxylate To 0.1moles of ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in 35ml. of 28 percent hydrochloric acid and 100 ml. of cracked ice tomaintain the temperature at C is added a solution of 7.1 g. (0.102moles) of sodium nitrite in 20 ml. of water. The reaction mixture isthen neutralized with sodium carbonate. This diazonium mixture is addedto a cuprous cyanide solution (prepared from 31.5 g. of copper sulfateand 16.2 g. of sodium cyanide in 75 ml. of water). 250 ml. of toluene isalso added and the mixture is stirred for one-half hour. The reaction isthen allowed to stir an additional 2 hours while warming gradually to50C. This is then cooled and the toluene separated, dried over sodiumsulfate and evaporated to dryness to obtain ethyl 4-cyano-5,6,7,8-tetrahydro-2- naphthylglyoxylate.

When ethyl 4-amino-5,6,7,8-tetrahydro-2- EXAMPLE 1O Ethyl4-fluoro-5,6,7,8-tetrahydro-Z-naphthylglyoxylate To 0.15 moles of ethyl4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate is added at 0C 44 ml.of 1.5 moles of concentrated hydrochloric acid. The reaction mixture ismaintained at 0C and the diazonium salt is prepared with 23.2 g. (0.32moles) of 95 percent sodium nitrite in 80 ml. of water. To this mixtureis rapidly added a solution of 10.4 g. (0.17 moles) of boric aciddissolved in 22 g. (0.66 moles) of 60 percent hydrofluoric acid. Thereaction mixture is then stirred for onehalf hour and filtered, washedwith 3 X 25 ml. of water, 2 X 25 ml. of methanol and 25 ml. of ether.The residual cake is then treated in vacuo. The treated cake is thenplaced in a distilling flask and heated to permit spontaneousdecomposition. After the decomposition, the residue is then fractionallydistilled to obtain ethyl 4-fluoro-5,6,7-tetrahydro-2-naphthylglyoxylate.

When ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 6, then thecorresponding products are obtained.

EXAMPLE 11 4-Hydroxy-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid To 4.5g. of ethyl 4-amino-5,6,7,8-tetrahydro-2- glyoxylate suspension in 125ml. of 80 percent hydrochloric acid and cooled to 0C is added dropwise asolution of 1.2 g. of sodium nitrite in 15 ml. of water. After aboutmin., 200 ml. of 50 percent hydrochloric acid is added portion wise andstirred for hours. The reaction mixture is then poured onto ice waterand extracted with chloroform, dried over sodium sulfate andconcentrated in vacuo. The residue is crystallized to obtain4-hydroxy-5,6,7,8-tetrahydro-2- naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

equimolar amounts of the compounds of Example 6,

then the corresponding products are obtained.

EXAMPLE 12 Ethyl 4-methoxy-5 ,6,7,8-tetrahydro-2-naplithylglyoxylate Toa stirred suspension of 0.01 moles of sodium hydride in 25 ml. of drydimethylformamide which has been cooled to 0C is added dropwise asolution of 0.01 moles of ethyl 4-hydroxy-5,6,7,8-tetrahydro-2-naphthylglyoxylate in 10 ml. of dimethylformamide. The reaction mixtureis stirred for 15 minutes and 0.015 moles of methyliodide is then addeddropwise. The mixture is allowed to stir overnight at room temperature.200 ml. of water is added and the resulting mixture is extracted wellwith ether. The ether extract is washed with water, dried over sodiumsulfate, evaporated to dryness and distilled to obtain ethyl 4-methoxy-S,6,7,8-tetrahydro-Znaphthylglyoxylate.

When ethyl 4-hydroxy-5,6,7,8-tetrahydro-2- naphthylglyoxylate in theabove example is replaced by equimolar amounts of the compounds ofExample 1 1, then the corresponding products are obtained.

When 0.01 moles of acetyl chloride is used in place of methyliodide inthe above reaction, then the product prepared is ethyl4-acetyloxy-5,6,7,8-tetrahydro-2- naphthylglyoxylate.

EXAMPLE 1 3 4-Bromo-5,6,7,8 tetrahydro-2-naphthylglyoxylic acid To 0.044moles of ethyl 4-amino-5,6,7,8-tetrahydro- 2-naphthylglyoxylatesuspension in 225 ml. of 40 perccent hydrobromic acid and cooled to 0Cis added dropwise a solution of 2.34 g. of sodium nitrite in 30 ml. ofwater. To this mixture is added a solution of 20 g. of cuprous bromidein 350 ml. of 40 percent hydrobromic acid portion wise and stirred for15 hours. The reaction mixture is then poured onto ice water, extractedwith chloroform, dried over sodiumsulfate and concentrated in vacuo. Theresidue is then crystallized to obtain 4-bromo-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 6, then thecorresponding products are obtained.

EXAMPLE l4 4-Iodo-5,6,7,8-tetrahydro-2-naphthylglyoxylic acid To .05moles of ethyl 4-amino-5,6,7,S-tetrahydro-Z- naphthylglyoxylatedissolved in a mixture of 50 g. of ice water and .06 moles ofconcentrated sulfuric acid at 0C is added a solution of 0.05 moles of 95percent sodium nitrite in 8 ml of water/Stirring is continued forone-half hour and then 1.5 ml. of concentrated sulfuric acid isadded..This solution is poured into an ice cold solution of 0.06 molesof potassium iodide in 10 ml. of water. To this is added 0.075 g. copperbronze with stirring and the solution is warmed slowly on a water bathto about C for 2 hours. After cooling to room temperature the reactionmixture is extracted thrice with 15 m1. portions of chloroform. This isthen washed with dilute thiosulfate solution, water. dried over sodiumsulfate and evaporated in vacuo. The residue is crystallized to obtain4-iodo-5.6,7.8-tetrahydro-2- naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are obtained.

EXAMPLE l5 4-Mercapto-5,6,7,8-tetrahydro-Z-naphthylglyoxylic acid To0.068 moles of ethyl 4-amino-5,6,7,8-tetrahydro- Z-naphthylglyoxylate in11.1 ml. of concentrated hydrochloric acid and 20 g. of ice is added 4.1g. of sodium nitrite in 2 ml. of water. This mixture is stirred for min.and then added gradually to an ice cold solution of 10.3 g. of potassiumethyl xanthate in 14 ml. of water. The reaction is gradually heated over45 mihutes to 50C and stirred an additional 45 minutes. The mixture isthen cooled, extracted with ether which is then washed with water,dilute sodium hydroxide and water, dried over sodium sulfate andevaporated in vacuo. The residue is dissolved in 35 ml. of boilingethanol to which is added gradually 13 g. of potassium hydroxide. Thereaction is refluxed an additional hour and then evaporated to drynessin vacuo. The residue is dissolved in water and extracted with ether.The alkaline phase is acidified with 6N sulfuric acid and extracted withether. The ether is washed with water, dried over sodium sulfate andevaporated to dryness to obtain 4-mercapto-S.6,7,8-tetrahydro-2-naphthylglyoxylic acid.

The ethyl ester of the product is formed by reaction with absoluteethanol containing a small amount of anhydrous hydrochloric acid.

When ethyl 4-amino-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by equimolar amounts of the compounds of Example 6,then the corresponding products are prepared.

EXAMPLE 16 Ethyl 4-methy1thio-5,6,7,8-tetrahydro-2-naphthy1glyoxylate To0014 moles of ethyl 4-mercapto-5,6,7,8- tetrahydro-2-naphthylglyoxylatein 40 ml. of water containing 0.65 g. of sodium hydroxide is added 2 ml.of dimethyl sulfate with stirring. The reaction mixture is graduallywarmed to 40C and stirred for 2 hours. The mixture is cooled andextracted with ether which is washed with water, dried and evaporated invacuo. The residue is distilled to obtain ethyl 4-methylthio-5,6,7.8-tetrahydro-2-naphthylglyoxylate.

When the above 4-methylthio-5,6,7,8-tetrahydro-2- naphthylglyoxylate istreated with 30 percent H 0 then the resultant product is ethyl4-methylsulfinyl- 5.6,7.8-tetrahydro-2-naphthylg1yoxylate or ethyl 4-methylsulfonyl-S,6,7.8-tetrahydro-2- naphthylglyoxylate.

When 4-mercapto-5,6,7,8tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by the compounds of Example 15, then thecorresponding products are prepared.

When an equimolar amount of acetyl chloride is used in place of dimethylsulfate in the above reaction, then the product prepared is ethyl4-acetylthio-5,6.7,8- tetrahydro-2-naphthylglyoxylate.

EXAMPLE l7 Ethyl 4-ch1oro-5,6,7,8-tetrahydro-2-naphthylglycolate Into aPaar hydrogenation bottle is added 0.144 mole of ethyl4-chloro-5,6,7,8-tetrahydro-2- naphthylglyoxylate, 2 ml. of 0.1M-ferrous sulfate solution; 220 ml. of isopropanol, and 1.0 g. of 84.1percent platinum oxide. The mixture is shaken for 2 hours at roomtemperature with hydrogen gas until 0.144 mole of hydrogen is absorbed.The catalyst is then filtered off and the solution is evaporated invacuo and the residue fractionally distilled to obtain ethyl4-ch1oro-5,6,7,8- tetrahydro-2-naphthylglycolate.

EXAMPLE 1 8 Ethyl 4-nitro-5,6,7,8-tetrahydro-2-naphthylglycolate Asodium borohydride solution 0.302 mole in 13 ml. of water containing 1drop of 10 N sodium hydroxide is added dropwise to a stirred solution of17.9 g. (0.0587 mole) of ethyl 4-nitro-5,6,7,8-tetrahydro-2-naphthylglyoxylate, methanol (50 ml.) and water (5 ml.) cooled in anice-water mixture. The solution is partially neutralized withurea-active acid solution 15 ml. each of acetic acid and urea 0.041mole). The pH after the addition is near neutral. The pH then isadjusted to acidic by addition of 18 N sulfuric acid (2.8 ml.). The gumproduct is extracted with ether. The ether extract is washed with 2 X 25ml. of saturated sodium bisulfite to remove the traces of initialcarbonyl compound and then dried over anhydrous sodium sulfite for 2hours. The drying agent is removed and the solvent is then removed toobtain ethyl 4-nitro-5,6,7,8- tetrahydro-2-naphthylglycolate.

When ethyl 4-nitro-5,6,7,8-tetrahydro-2- naphthylglyoxylate in the aboveexample is replaced by an equimolar amount of the glyoxylate esters ofExamples l-17, then the corresponding glycolate product is prepared.

EXAMPLE 19 4-Ch1oro-5,6,7,8-tetrahydro-Z-naphthylglycolic acid To asolution of 0.144 moles of ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate dissolved in 220 ml. ofisopropanol is added 38 g. (0.7 mole) of potassium hydroxide. Thismixture is then heated at reflux temperature in a nitrogen atmosphere.The solution is concentrated in vacuo to a viscous oil, which is thendissolved in 500 ml. of water and filtered. The filtrate is acidifiedwith 10 percent HCl and the precipitate is taken up in ether. The etherlayer is dried, filtered and the filtrate concentrated to dryness.Recrystallization of residue from benzenecyclohexane 1:1 gives 4-chloro-S,6,7,8-tetrahydro-2-naphthylglycolic acid.

EXAMPLE 20 4-Cyano-5,6,7,8-tetrahydro-2-naphthylglycolic acid A solutionof 0.01 moles of benzyl 4-cyano-5,6,7,8-

tetrahydro-2-naphthylglycolate dissolved in ml. of acetic acid andcontaining 0.01 mole of hydrogen chloride is shaken with hydrogen over a5 percent Pd carbon catalyst until 0.01 moles of hydrogen is absorbed.The catalyst is then filtered and the solution is evaporated to drynessand crystallized to obtain 4-cyano-5,6,7,S-tetrahydro-Z-naphthylglycolic acid.

EXAMPLE 21 Ethyl a-methyl-4-chloro-5 ,6,7,8-tetrahydro-2-naphthylglycolate A solution of methylmagnesium iodide is prepared from6.7 g. (0.047 mole) of methyl iodide, 1.24 g. (0.051 g-atom) ofmagnesium turnings and 40 ml. of anhydrous ether. This solution is addedover a period of l hour to a solution of 0.05 mole of ethyl 4chloro-5,6,7,8-tetrahydro-2-naphthylglyoxylate. The addition is carried outwith vigorous stirring at -5C. The mixture is then allowed to warm toroom temperature over hours. The mixture is poured into an ice-coldsolution of 0.2 M-sulfuric acid. The ether layer is separated, extractedwith 1 percent sulfuric acid, dried over magnesium sulfate, filtered andevaporated to obtain ethyl a-methyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate.

When ethyl 4-chloro-5,6,7,8-tetrahydro-2- naphthylglyoxylate in theabove example is replaced by the glyoxylates of this invention, then thecorresponding a-methyl products are prepared.

When the Grignard reagent used is ethylmagnesium iodide, propylmagnesiumiodide or butylmagnesium iodide, then the corresponding product isprepared.

EXAMPLE 22 l 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid To aboiling solution of 29.4 g. (0.10 mole) of cinchonidine in 1 liter ofabsolute ethanol is added a boiling solution of 0.10 mole of C114-chloro-5,6,7,8- tetrahydro-Z-naphthylglycolic acid in 500 ml. ofabsolute ethanol. The solution is stirred briefly then allowed to coolto room temperature overnight. The precipitate is collected and washedwith 2 X ml. of ethanol and air dried. Recrystallization fromisopropanol gives white needle crystals. This material is hydrolyzedwith 200 ml. of 1.2 NNCl. The white solid is collected, washed with 3 X50 ml. water and dried at 55C overnight. Recrystallization frombenzenecyclohexane 3:2 gives 14-chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid.

When modifications of the above resolution procedure are followed but dl4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolic acid is replaced by anequimolar amount of the dl glycolic acids and esters of Examples 17-21,then the corresponding l-isomer is prepared.

EXAMPLE 23 d 4-Chloro-5,6,7,8-tetrahydro-Z-naphthylglycolic acid Thecombined ethanol and isopropanol filtrates from Example 22 areevaporated to dryness. This material is triturated with 1 liter ofboiling acetone. The material which does not go into solution isfiltered off. The filtrate is evaporated to dryness and hydrolyzed with100 ml. of 1.2 N-HCL. The precipitate is collected, washed with 3 X 25ml. of water, and dried at 55C. Recrystallization frombenzene-cyclohexane 3:2 gives d4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid.

When modifications of the above resolution procedure is followed but dl4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolic acid is replaced by anequimolar amount of the (11 glycolic acids and esters of Examples 17-21,then the corresponding d-isomer is prepared.

EXAMPLE 24 4-Chloro-5,6,7,S-tetrahydro-2-naphthylglycolic acid, sodiumsalt A solution of 12.4 g. of sodium bicarbonate in ml. of water isadded dropwise to a stirred solution of 0.164 moles of4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolic acid in ml. of methanol.The solvent is removed in vacuo and the residue is dried by repeateddistillations with anhydrous ethanol. The crystalline residue istriturated with ether (100 ml.), collected and washed with ether. Theresidue is dried in a vacuum desiccator to obtain 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid, sodium salt.

When an equimolar amount of sodium bicarbonate in the above reaction isreplaced by the compounds of Table I below, then the corresponding saltis prepared.

Table I sodium hydroxide potassium hydroxide calcium hydroxide potassiumcarbonate magnesium bicarbonate When the dl, d and l glycolic acidcompounds of this invention are used in the above reaction, then thecorresponding salt is prepared.

EXAMPLE 25 4-Chloro-5,6,7,8-tetrahydro-2-naphthylglycolic acid,diethylammonium salt below, then the corresponding product is prepared.

Table l dimethylamine u-methylbenzylamine fl-hydroxyethylaminecyclohexylamine piperazine triethylamine piperidine phenethylamine Whenthe dl, d and l glycolic acids of this invention are used in the abovereaction, then the corresponding salt is prepared.

EXAMPLE 26 N-isopropyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide Ethyl 4-chloro-5 ,6 ,7 8-tetrahydro-2-naphthylglycolate (0.1 mole) is stirred with 20 ml. of isopropylamine atabout 35C with stirring overnight and the temperature is then raised toreflux for 28 hours. The reaction mixture is evaporated in vacuo and theresidue distilled to obtain N-isopropyl-4-chloro- 5 ,6,7,8-tetrahydro-Z-naphthylglycolamide.

25 When isopropylamine in the above reaction is replaced by an equimolaramount of the compound of Table I. below then the corresponding productis prepared.

Table l diethylamine isothiazolidine Ethylmethylamine piperidineT-butylamine morpholine cyclopropylamine Nmethylpiperazine Nmeth\'lhomopiperazine EXAMPLE 27 Ethyl a,4 dichloro-,6,7,8-tetrahydro-2-naphthylacetate A mixture of 0.747 mole of ethyl4-chloro-5,6,7,8- tetrahydro-Z-naphthylglycolate is stirred with 106.67g. (0.895 mole) of thionyl chloride at room temperature for 24 hours andthen heated to reflux for 6 hours. The cold reaction mixture is pouredinto 1125 ml. of icecold water with stirring. The mixture is extractedwith 800 ml. of ether. The ethereal solution is washed with 450 ml. ofcold saturated sodium hydrocarbonate solution followed by washing twice,each time with 250 ml. of cold water. The ethereal solution is driedover anhydrous sodium sulfate and filtered. The solvent is re moved invacuo to obtain ethyl a.4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetate.

EXAMPLE 28 When the procedure of Example 27 is followed but ethyl4-chloro-5,6,7,8-tetrahydro-Z-naphthylglycolate is replaced by the dl, dand l glycolates of this invention, then the corresponding dl, d and la-chloroacetate products are prepared.

EXAMPLE 29 When the procedure of Example 27 is followed by ethyl4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate is replaced by theamides of Example 26, then the corresponding product is obtained.

EXAMPLE 30 oz4-Dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid Amixture of 0.167 moles of the ethyl a,4-dichlor0-5,6,7,8-tetrahydro-2-naphthylacetate and 160 ml. of glacial acetic acidcontaining 40 ml. of 37 percent hydrochloric acid is refluxed for hours.The mixture is concentrated under reduced pressure to give a gummyresidue. The latter material is dissolved in 300 ml. of n-hexane, washedwith ice-cold water (100 ml. total), dried over sodium sulfate andfiltered. The hexane is removed to givea,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetic acid.

EXAMPLE 31 When the procedure of Example 30 is followed but ethyla,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetate is replaced by thedl, d and l a-chloroacetates of this invention, then the correspondingdl, d and l a-chloroacetic acids are prepared.

EXAMPLE 32 a,4-Dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid, sodiumsalt A solution of 12.4 g of sodium bicarbonate in ml. water is addeddropwise to a stirred solution of 0.164 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetic acid in cc. ofmethanol. The solvent is removed in vacuo and the residue is dried byrepeated distillations with anhydrous ethanol. The crystalline residueis triturated with ether (100 cc.), collected on a filter, and washedwith ether. Drying in a vacuum desiccator affords a,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid, sodium salt.

EXAMPLE 33 a,4-Dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid,diethylammonium salt Anhydrous diethylamine (0.1 1 moles) is addeddropwise to a stirred solution of a,3-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid (0.10 moles) in 100 ml. of n-hexane at0C. The precipitate is collected on a filter, washed with n-hexane, anddried in a vacuum desiccator to obtaineda,4-dichloro-5,6,7,8-tetrahydro-' 2-naphthylacetic acid, diethylammoniumsalt.

When diethylamine in the above reaction is replaced by an equimolaramount of the compounds of Table 1, below, then the correspondingproduct is prepared.

EXAMPLE 34 N-isopropyla,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide A mixture of 0.016mole of ethyl a,4-dichloro- 5,6,7,8-tetrahydro-Z-naphthylacetate and 5.5ml. of anhydrous isopropylamine are stirred over Linde 4A molecularsieve for 16 hours at room temperature. The reaction mixture is filteredand excess isopropylamine is removed in vacuo. The residue is taken upin ether and washed three times with 15 ml. of 10 percent hydrochloricacid. The ether layer is dried over sodium sulfate, filtered, and theether is removed. The residue is triturated with n-hexane and theprecipitate is collected to obtain N-isopropyla.4-dichloro-5,6,7,8-tetrahydro- Z-naphthylacetamide.

When isopropylamine in the above reaction is replaced by an equimolaramount of the compound of cyclopropylamine N-methylpiperazineN-methylhomopiperazine When isopropylamine in the above reaction isreplaced by ammonia, methylamine or dimethylamine and the reactioncarried out in a bomb at 150C, then the product prepared isa,4-dichloro-5,6,7,8-

tetrahydro-2-naphthylacetamide, N-methyl-a,4-dichloro-S,6,7,S-tetrahydro-2-naphthylacetamide or N,N-dimethyla,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetamide.

When the dl, d or 1 a-chloroacetates of this invention are used in theabove reaction, then the corresponding amide is prepared.

EXAMPLE 35 Ethyl a-bromo-4-chloro-5 ,6,7 ,8-tetrahydro-2-naphthylacetate To 0.0476 moles of ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate there is added slowly with stirring at40-50C 23 g. (0.053 moles) of phosphorus pentabromide. The mixture isstirred at room temperature for 16 hours, then diluted with 70 ml. ofpetroleum ether, and poured into 125 ml. of ice-cold water. The organicphase is separated, washed with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous sodium sulfate, filtered andthe solvent removed in vacuo to obtain ethyl a-bromo-4-chloro-S,6,7,8-tetrahydro-2-naphthylacetate.

When ethyl 4-chloro-5,6,7,8-tetrahydro-2- naphthylglycolate in the aboveprocedure is replaced by d ethyl 4-chloro-5,6,7,8-tetrahydro-2naphthylglycolate, l ethyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolate or N-isopropyl 4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide, then the products prepared are l ethyla-bromo-4-chloro-5,6,7,8- tetrahydro-2-naphthylacetate, d ethyla-brorno- 4- chloro-S,6,7,8-tetrahydr-2-naphthylacetate or N- isopropyla-bromo-4-ch1oro-5,6,7,8-tetrahydro-2- naphthylacetamide When the aboveprocedure is followed using the various glycolates and glycolamides ofthis invention, then the corresponding oz-bromoacetates anda-bromoacetamides are prepared.

EXAMPLE 36 When the a-bromoacetates of Example 35 are hydrolyzedaccording to the procedures of Examples 303 1 then the corresponding d],d and l oz-bromo-4-chloro- 5,6,7,8-tetrahydro-Z-naphthylacetic acidcompounds and the various oz-bromoacetic acids are prepared.

EXAMPLE 37 When the oz-bromoacetic acid compounds are reacted accordingto the procedures of Examples 32-33, then the correspondingoz-bromoacetic acid salts are prepared.

EXAMPLE 38 Ethyl a-fluoro-4-chloro-5 ,6,7 ,8-tetrahydro-2-naphthylacetate EXAMPLE 39 When the a-fiuoroacetates of Example 38 arehydrolyzed according to the procedures of Examples 30-31, then thecorresponding a-fluoro-4-chloro-5,6,7,8- tetrahydro-2-naphthylaceticacid compound and the various a-fluoroacetic acids are prepared.

EXAMPLE 40 When the oz-fluoroacetic acid compounds are reacted accordingto the procedures of Examples 3233, then the correspondinga-fluoroacetic acid salts are prepared.

EXAMPLE 4 l Ethyl a-iodo-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate Amixture of 0.1 moles of ethyl a-bromo-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetate and 150 g. of sodium iodide in 1liter of anhydrous acetone is refluxed for 4 hours. The reaction mixtureis then evaporated to dryness and extracted with ether. The ether isthen washed with water, dried and evaporated to dryness to obtain ethyloz-iodo-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetate.

When the above procedure is followed using the various a-bromoacetatesand a-bromoacetamides of this invention then the correspondinga-iodoacetates and oz-iodoacetamides are prepared.

EXAMPLE 42 When the oz'iodoacetates of Example 41 are hydrolyzedaccording to the procedures of Examples 303 1 then the correspondingaiodo-4-chloro-5,6,7,8- tetrahydro-2-naphthylacetic acid compound andthe various a'iodoacetic acids are prepared.

EXAMPLE 43 When the a-iodoacetic acid compounds are reacted according tothe procedures of Examples 3233, then the corresponding a-iodoaceticacid salts are prepared.

EXAMPLE 44 a-Mercapto-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acidA mixture of .05 moles of a,4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and 5 g. of sodium hydrosulfide in ml.of absolute ethanol and under a nitrogen atmosphere is stirred for 15hours. The mixture is then acidified with 6 N hydrochloric acid. The

solvent is removed in vacuo and the residue is extracted into ether.washed with water, saturated sodium chloride solution. dried andevaporated to dryness to obtaina-mercapto-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acid.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-mercaptoacetatesand a-mercaptoacetamides are prepared.

EXAMPLE 45 a-Methylthio-4-chloro-5,6,7,8-tetrahydro2- naphthylaceticacid Methyl mercaptan is bubbled into a solution of 18.4 g. of potassiumt-butoxide in 100 ml. of t-butanol for three-quarter hours and under anitrogen atmosphere. To this is added 0.041 moles ofa.4-dichloro-5,6,7,8- tetrahydro-2-naphthylacetic acid in 60 ml of drytetrahydrofuran. The mixture is then refluxed for 3 hours and allowed tostir at room temperature for 15 hours, acidified with 30 ml. of 6 Nhydrochloric acid. The solvent is removed in vacuo and the residueextracted into ether, washed with water, saturated sodium chloridesolution. dried and evaporated to dryness to obtaina-methylthio-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acid.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-methylthioacetatesand a-methylthioacetamides are prepared.

EXAMPLE 46 a-Acetylthio-4-chloro-5,6,7,8-tetrahydro-2- naphthylaceticacid To a solution of 600 ml. of anhydrous ethanol and 21 g. (0.317moles) of potassium hydroxide is added 45 ml. of thioacetic aciddropwise. To this mixture is then added 0.244 moles of04,4-dichloro-5,6,7,8-tetrahydro- Z-naphthylacetic acid and stirring iscontinued for 15 hours. The solid which forms is filtered off and washedwith ethanol. The filtrate is evaporated to dryness and the residue isdissolved in 500 ml. of ether and washed several times with water.Drying the ether and evaporation to dryness results ina-acetylthio-4-chloro-5,6,7,8- tetrahydro-Z-naphthylacetic acid.

In a similar manner, the a-propionylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid compounds are prepared.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-acetylthioacetatesand a-acetylthioacetamides are prepared.

EXAMPLE 47 a-Benzoylthio-4-chloro-5 ,6,7,8-tetrahydro-2- naphthylaceticacid To 17.5 ml. of 2N alcoholic potassium hydroxide solution (0.035mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution iscooled to room temperature and to this is added in small portions 0.035mole of a,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetic acid. Thereaction mixture is stirred at room temperature for 25 hours, then thesolvent is removed, the residue dissolved in ether, filtered and washedwith cold water. The ethereal solution is then dried over magnesiumsulfate and evaporated to dryness to obtaina-acetylthio-4-chloro-5,6,7,8- tetrahydro-2-naphthylacetic acid.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-benzoylthioacetatesand a-benzoylthioacetamides are prepared.

EXAMPLE 48 Ethyl a-thioacetylthio-4-chloro-5 ,6,7,8-tetrahydro-2-naphthylacetate A mixture of 0.2 moles of sodium dithioacetate and 0.12moles of ethyl a,4-dichloro-5,6,7,8-tetrahydro-2- naphthylacetate in 300ml. of absolute ethanol is stirred at room temperature for 15 hours. Thereaction mixture is filtered, washed with absolute ethanol andevaporated to dryness in vacuo. The residue is treated with ether,filtered and evaporated to dryness to obtain ethyla-thioacetylthio-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetate.

When the a-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the correspondinga-thioacetylthioacetates and a-thioacetylthioacetamides are prepared.

When sodium dithioformate is used in the above procedure in place ofsodium dithioacetate then the product prepared is ethyla-thioformylthio-4-chloro- 5,6,7,8-tetrahydro-2-naphthylacetate.

EXAMPLE 49 a-Thiocyanato-4-chloro-5 ,6 ,7,8-tetrahydro-2- naphthylaceticacid To a solution of 300 ml. of anhydrous ethanol and 0.15 moles ofsodium thiocyanate is added 0.12 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid and stirred for 15hours. The reaction mixture is filtered and washed with absoluteethanol. The filtrate is evaporated to dryness, the. residue isdissolved in 250 ml. of ether and washed several times with water. Theether is then dried evaporated to dryness to obtainwthiocyanato-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acid.

When the a-chloroacetate and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-thiocyanatoacetatesand a-thiocyanatoacetamides are prepared.

EXAMPLE 50 a-Sulfo-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid,disodium salt To a solution of 250 ml. of anhydrous ethanol and 0.12moles of sodium sulfite is added 0.1 moles of a,4-dichloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid, sodium salt. Thereaction mixture is stirred for 15 hours, filtered and the residueworked with ethanol. The filtrate is evaporated to dryness to obtainoz-sulfo-4- chloro-S,6,7,8-tetrahydro-2-naphthylacetic acid, disodiumsalt.

When sodium sulfinate is used in the above procedure in place of sodiumsulfite, then the product obtained isa-sulfino-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acid, disodiumsalt.

When the a-chloroacetates and oz-chloroacetamides of this invention areused in the above reactions, then the corresponding oz-sulfo anda-sulfinoacetates and amides are prepared.

EXAMPLE 51 Ethyl a-thiosulfo-4-chloro-5 ,6,7,8-tetrahydro-2-naphthylacetate, sodium salt A mixture of 0.023 moles of ethyla,4-dichloro- 5,6,7,8-tetrahydro-Z-naphthylacetate and 5.7 g. of sodiumthiosulfate pentahydrate in 75 ml. of 40:45 wateralcohol mixture isrefluxed for 2 hours. An additional 0.8 g. of sodium thiosulfatepentahydrate is then added and refluxing continued another one-halfhour. The reaction mixture is then evaporated to dryness in vacuo,azeotroped with ethanol and evaporated to dryness in vacuo again. Theresidue is triturated with ether, filtered and evaporated to dryness.The residue is then triturated with hexane and the resultant gum isdissolved in alcohol and evaporated to dryness in vacuo to obtain ethyla-thiosulfo-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetate, sodium salt.

When the oz-chloroacetates and a-chloroacetamides of this invention areused in the above reaction, then the corresponding a-thiosulfoacetatesand a-thiosulfoacetamides are prepared.

EXAMPLE 52 oz-Amidinothio-4-chloro-5,6,7,8-tetrahydro-2- naphthylaceticacid, hydrochloride Thiourea 15.2 g. (0.2 moles) is dissolved in 150 ml.of absolute ethanol and to this is added 0.11 moles ofa,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetic acid. The mixture isstirred for 15 hours at C. The mixture is then filtered to obtaina-amidinothio-4-chloro- 5,6,7,8-tetrahydro-2-naphthylacetic acid,hydrochloride.

When the a-chloroacetates and acetamides of this invention are used inthe above procedures then the corresponding a-amidinoacetates andacetamides are prepared.

EXAMPLE 53 a-Ethoxythiocarbamylthio-4-chloro-5,6,7,8-tetrahydro-Z-naphthylacetic acid EXAMPLE 54a-Ethoxycarbonylthio-4-chloro-5,6,7,8-tetrahydro-2- naphthylacetic acidA solution of a-mercapto-4-chloro-5,6,7,8-2- naphthylacetic acid (0.02moles) in 25 ml. of pyridine is cooled in an ice bath. To this is addeddropwise 2.1 mol (0.022 moles) of ethyl chloroformate. The mixture isthen stirred for 2 hours, diluted with ether and filtered. The mixtureis basified with percent sodium bicarbonate solution. The alkalinemixture is worked with ether, then acidified with 10 percenthydrochloric acid, washed with ether, dried and filtered. The solvent isremoved and the residue is triturated with hexane to obtaina-ethoxycarbonylthio-4-chloro-5,6,7,8- tetrahydro-2-naphthylacetic acid.

When the a-mercaptoacetates and acetamides of this invention are used inthe above procedure then the corresponding a-ethoxycarbonylthioacetatesand acetamides are prepared.

EXAMPLE 55 oz-Diethylcarbamylthio-4-chloro-5 ,6,7,8-tetrahydro-2-naphthylacetic acid A solution of a-mercapto-4-chloro-5,6,7,8-2-naphthylacetic acid (0.2 moles) in 25 ml. of pyridine is cooled in anice bath. To this is added dropwise 0.022 moles ofdiethylcarbamylchloride. The mixture is then stirred for 2 hours,diluted with ether and filtered. The mixture is then basified with 10percent sodium bicarbonate solution. The alkaline mixture is washed withether, acidified with 10v percent hydrochloric acid, extracted withether which in turn is washed with cold water, dried and evaporatedtodryness. Trituration with hexane results inq-diethylcarbamylthio-4-chloro- 5,6,7,8-tetrahydro-2-naphthylaceticacid.

When diethylcarbamylchloride is replaced in the above procedure bycarbamyl chloride (prepared in situ from potassium cyanate and anhydroushydrogen chloride in anhydrous chloroform), ethylcarbamyl chloride ordimethylcarbamyl chloride, then the products prepared areoz-carbamylthio-4-chloro-5,6,7,8- tetrahydro-Z-naphthylacetic acid,a-ethylcarbamylthio-4-chloro-5,6,7,8-tetrahydro+Z-naphthylacetic acid ora-dimethylcarbamyl-thio-4-chloro-5 ,6,7 8 -tetrahydro- Z-naphthylaceticacidl When the a-mercaptoacetates and acetamides of this invention areused in the above procedure then the correspondinga-carbamylthioacetates and acetamides are prepared.

EXAMPLE 56 When the procedure of Example 55 is followed butdiethylcarbonate is replaced by succinic anhydride, maleic anhydride orphthalic anhydride, then the products prepared are abutyrylthio-4-chloro-5,6,7,8- tetrahydro-2-naphthylacetic acid,a-butenoylthio-4- chloro-S,6,7,8-tetrahydro-2-naphthylacetic acid anda-( o=carboxybenzoylthio )-4-chloro-5 ,6,7,8-tetrahydro-2-naphthylacetic acid.

When the various a-mercaptoacetates and acetamides of this inventionareused in the above procedure, then the corresponding product is prepared.

EXAMPLE 57 When a-methylthio-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid is treated with 30 percent hydrogen peroxide, thenthe resultant product isa-methylsulfinyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetic acid ora-methylsulfonyl-4-chloro-S,6,7,8-tetrahydro- Z-naphthylacetic acid.

I claim:

1. A compound of the formula

1. A COMPOUND OF THE FORMULA 2.L/ARALKYLAMINO OR CYCLOLOWERALKYLAMINO 2.A compound according to claim 1 where R is chloro.
 3. Alpha,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide. 4.4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 5.N-isopropyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 6.N,N-diethyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 7.N-ethyl-N-methyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 8.N-t-butyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 9.N-cyclopropyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 10.N-methyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 11.N,N-dimethyl-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 12.N-isopropyl- Alpha ,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide.13. N,N-diethyl- Alpha,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide. 14.N-ethyl-N-methyl- Alpha,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide.
 15. N-t-butyl- Alpha,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide.
 16. N-cyclopropyl-Alpha ,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide.
 17. N-methyl-Alpha ,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide. 18.N,N-dimethyl- Alpha ,4-dichloro-5,6,7,8-tetrahydro-2-naphthylacetamide.19. N-isopropyl- Alpha-bromo-4-chloro-5,6,7,8-tetrahydro-2-naphthylglycolamide. 20.N-isopropyl- Alpha-fluoro-4-chloro-5,6,7,8-tetrahydro-2-naphthylacetamide.